Dose-limiting Adverse Events Research Articles

Patient characteristics associated with dose-limiting sunitinib adverse events

e16110 Background: Sunitinib, an inhibitor of multiple tyrosine kinases, is FDA approved for metastatic renal cell cancer (mRCC). Though better tolerated than historical therapies, sunitinib is associated with adverse events (AEs) that may require dose modifications (DM). We sought to identify 1) baseline patient (pt) characteristics that predispose for DM, 2) the most common AEs requiring DM in a non-protocol setting, and 3) the impact of dose limiting AEs on treatment continuation. Methods: Single-center, retrospective chart review. Pts ≥ 18 years of age with mRCC of clear-cell histology on sunitinib therapy with active follow-up at MDACC were eligible. Univariate and multivariate logistic regression analysis of 66 pt variables (demographics, laboratory analysis, past medical and treatment history, etc) and dose-limiting AEs was completed, with a 6 month endpoint of sunitinib continuation, alternative therapy, or death. Results: From January 1, 2006 through September 30, 2007, 146 pts were identified meeting eligibility criteria. By univariate analysis, increased age (p=0.04; OR 1.04, 1.002–1.081 CI) and elevated BUN (p=0.03; OR 1.06, 1.006 –1.108 CI) were directly associated with increased incidence of dose-limiting AEs. ECOG PS of 2 (p=0.04; OR 0.3, 0.114–0.951 CI) was associated with a decreased incidence of dose limiting AEs. In a multivariate analysis, only BUN remained significant. 57% of patients (n= 83) had dose-limiting AEs. DM were often attributed to multiple AEs (55%), with fatigue, mucositis, hand-foot syndrome and nausea being the most common. At 6 months follow-up, 63% of pts with dose-limiting AEs remained on sunitinib vs. 37% (p=0.18). There was no difference in death rate at 6 months between the two groups. Conclusions: Elevated baseline BUN is associated with an increased rate of DM in patients with RCC receiving sunitinib. Despite the high-incidence of AEs, pts can be maintained on sunitinib with DM and without an adverse impact on outcome. Whether specific AEs are biologic indicators of activity should be evaluated in a larger clinical trial. [Table: see text]

Effect of Recombinant Adenovirus-p53 Combined With Radiotherapy on Long-Term Prognosis of Advanced Nasopharyngeal Carcinoma

To centrally assess the safety, efficacy, and 6-year follow-up of recombinant adenovirus-p53 (rAd-p53) combined with radiotherapy (RT) for patients with nasopharyngeal carcinoma (NPC). A randomized controlled clinical study on rAd-p53 combined with RT in 42 patients with NPC was compared with a control group of 40 patients with NPC treated with RT alone. In the group receiving rAd-p53 combined with RT, rAd-p53 was intratumorally injected once a week for 8 weeks. Concurrent RT (70 Gy in 35 fractions) was given to the nasopharyngeal tumor and neck lymph node. Patients and tumors were monitored for adverse events and responses. rAd-p53-specific p53 mRNA was detected in postinjection of rAd-p53 biopsies from 16 (94.1%) of 17 patients. Upregulation of p21/WAF1 and Bax and downregulation of vascular endothelial growth factor were observed in postinjection tumor biopsy. Complete response rate in the group receiving rAd-p53 combined with RT was observed at 2.73 times that of the group receiving RT alone (66.7% v 24.4%). Six-year follow-up data showed that rAd-p53 significantly increased the 5-year locoregional tumor control rate by 25.3% for patients with NPC treated with irradiation (P = .002). The 5-year overall survival rate and 5-year disease-free survival rate of the group receiving rAd-p53 combined with RT were 7.5% (P = .34) and 11.7% (P = .21) higher than those of the group receiving RT alone. No dose-limiting toxicity or adverse events appeared, except for transient fever after rAd-p53 administration. In patients with NPC, rAd-p53 was safe and biologically active. Our results indicated that rAd-p53 improves radiotherapeutic tumor control and survival rate in patients with NPC.

Weekly Treatment with a Combination of Bendamustine and Bortezomib in Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma: A Single- Center Phase 1/2 Study.

Besides its established role in the treatment of patients with multiple myeloma, the proteasome inhibitor bortezomib is active in patients with a variety of indolent non-Hodgkin's lymphomas, notably mantle cell lymphoma and follicular lymphoma. Bendamustine was originally designed as a bifunctional anticancer compound combining an alkylating and an antimetabolite function. It has strong efficacy in non-Hodgkin's lymphoma and multiple myeloma, and apparently low cross-resistance with other alkylating agents. This open label, single-center phase 1/2 study evaluated a weekly combination of bortezomib and bendamustine in patients with relapsed or refractory indolent non-Hodgkin's lymphoma. The primary endpoint was to define the maximal tolerated dose (MTD). Secondary endpoints were tolerability and response. On days 1, 8, 15, and 22 of a 35-day cycle, patients received intravenous bolus bortezomib 1.6 mg/m2 for a maximum of 3 cycles. Bendamustine was administered as 30-min. intravenous infusion on days 1, 8, and 15. Dose escalation was started at a dose of 60 mg/m2 bendamustine. Response was assessed at the end of study treatment. Four patients entering the first dose level showed no dose-limiting toxicity (DLT). Thereupon, bendamustine dosage was increased to 80 mg/m2. In 3 out of 5 patients, DLT was observed. Dose-limiting adverse events were grade 3 diarrhea with dehydration, fatigue, and grade 4 thrombocytopenia, respectively. Adverse events with an overall incidence of ≥20% were diarrhea, nausea, vomiting, thrombocytopenia, and fatigue. There were no infectious or dose-limiting neurological adverse events. The 9 patients (7 females) in the phase 1 part of this trial, 5 with relapsed, 4 with refractory stage III (n=2) or stage IV (n=7) disease, received a median of 2 treatment cycles (range 2–3). Median age was 71 yrs (range 55–85). Detailed histological diagnoses were mantle cell lymphoma (n=4), follicular lymphoma (n=4), and Waldenstroem's macroglobulinemia (n=1). All patients were pretreated (median 3 lines of treatment, range 2–8). Prior treatments comprised rituximab (n=7), anthracyclines (n=4), ibritumomab tiuxetan (n=2), bortezomib (n=2), and autologous stem cell transplantation (n=1). The reasons for not completing the planned 3 treatment cycles were DLT (n=2), and disease progression (n=3). As best response, partial remission was achieved in 6 patients, while disease progressed in 3 patients. Among the different types of lymphoma, partial remissions were observed in all 4 mantle cell lymphoma patients, 1 out of 4 follicular lymphoma patients, and in the Waldenstroem's macroglobulinemia patient. The trial's phase 2 part is currently ongoing. In conclusion, weekly bortezomib and bendamustine (1.6 mg/m2 d1, 8, 15, & 22 and 60 mg/m2 d1, 8, & 15 q5w, respectively) was found to have acceptable toxicity. Moreover, this study demonstrates initial evidence of efficacy of the combination in heavily pretreated patients with indolent non-Hodgkin's lymphoma, particularly mantle cell lymphoma.

Use of Leflunomide in the Treatment of Polyomavirus BK-Associated Nephropathy

To review the available literature describing the use of leflunomide for the treatment of polyomavirus BK-associated nephropathy (BKVAN) in renal transplant recipients. Relevant literature was obtained through MEDLINE (1950-May 2008) and Science Citation Index Expanded (1900-May 2008) by using search terms leflunomide, Arava, polyomavirus, polyoma, BK virus, and transplant. Additional articles were identified through a manual search of the reference lists of the articles obtained. All articles that were written in English and discussed leflunomide use for BKVAN in renal transplant recipients were evaluated. Case reports and in vitro studies were included in this review. BKVAN has emerged as a problematic infectious complication with limited treatment options in renal transplant recipients. Leflunomide, used off-label for refractory BKVAN, is postulated to possess both antiviral and immunosuppressive properties. Two in vitro culture studies, 5 case reports/series, 2 retrospective cohort studies, and 3 prospective observational trials that described leflunomide use in BKVAN were identified. Available literature suggests that leflunomide at target blood concentrations of around 40 mg/L, in addition to immunosuppressive reduction, reduces BK viremia/viruria and graft failure, with few dose-limiting adverse events. It is highly recommended that routine complete blood cell counts, hepatic function panels, and drug concentrations be monitored to detect toxicity. Leflunomide appears to be promising as adjunctive treatment of BKVAN in renal transplant patients. Due to the lack of controlled randomized trials, however, use of leflunomide as first-line treatment cannot be routinely recommended.

A mouse model for glucocorticoid‐induced osteonecrosis: Effect of a steroid holiday

Glucocorticoid-induced osteonecrosis is a common and dose-limiting adverse event. The goal of this study was to establish a mouse model of glucocorticoid-induced osteonecrosis suitable for testing the effects of different treatment strategies on its frequency. Fourteen murine strains were screened using various glucocorticoids, routes of administration, and diets. Four-week-old male BALB/cJ mice were treated with oral dexamethasone for up to 12 weeks either by continuous dosing or by discontinuous dosing, with or without asparaginase. Histopathological features of the distal femurs were examined by light microscopy. Osteonecrotic lesions were characterized by empty lacunae and osteocyte ghosts in trabecular bone surrounded by necrotic marrow and edema. The incidence of dexamethasone induced osteonecrosis in BALB/cJ mice was 40-45% (4/10 or 5/11) at 12 weeks. The frequency of osteonecrosis trended lower after discontinuous compared to continuous dosing for 12 weeks (8 vs. 45%) (p = 0.06) despite comparable cumulative plasma exposure. Asparaginase hastened the occurrence of osteonecrosis, which was observed as early as 4 weeks and the incidence was 50% after 6 weeks. A mouse model of glucocorticoid-induced osteonecrosis was established. Discontinuous was less osteonecrotic than continuous dexamethasone treatment, consistent with the possible benefits of a "steroid holiday" seen in clinical settings. Moreover, asparaginase hastened osteonecrosis, indicating that drugs may interact with glucocorticoids to affect osteonecrosis risk.

Caring for the treatment-experienced breast cancer patient: The pharmacist’s role

The number of options for the management of metastatic breast cancer has expanded considerably during the past few years and are discussed here. New treatments have helped to palliate cancer symptoms and improve quality of life for many patients, but they also are associated with several clinically significant adverse events, including myelosuppression, nausea and vomiting, and neuropathy. Neutropenia often develops within a few days of the onset of chemotherapy and is associated with an increased risk of serious infection, hospitalization, treatment delays, and increased treatment costs. Anemia affects many patients with metastatic breast cancer and may result in significantly diminished quality of life. Chemotherapy-induced nausea and vomiting (CINV) is consistently rated by patients as among the most distressing symptoms associated with cancer treatment. The risk of nausea and vomiting varies considerably among different chemotherapy regimens, and guidelines for the prevention of CINV emphasize the importance of developing an antiemesis regimen that is based on the emetogenic potential of the chemotherapy regimen. Peripheral neuropathy is often the dose-limiting adverse event with many cancer therapies. Neuropathy may affect the sensory or motor nerves and produces a broad range of symptoms. Due to the increase in the number of oral medications used in cancer therapy in recent years, patient adherence to treatment has become increasingly important. Pharmacists have several important roles in helping patients with breast cancer to attain the best possible treatment outcomes and reducing the impact of adverse events. Some of these roles include patient education, participating in the development of institutional guidelines for the management of adverse effects, ensuring the appropriate laboratory tests have been performed, reconciliation of medications for patients who are hospitalized, and helping to improve treatment adherence for patients who are using oral therapies.

Pupillography as a sensitive, noninvasive biomarker in healthy volunteers: first-in-man study of BAY 63–9044, a new 5-HT1A-receptor agonist with dopamine agonistic properties

BAY 63-9044 is a new full 5-HT(1A)-agonist with functional dopamine agonist properties aimed for the treatment of Parkinson's disease. This first-in-man study investigated the pharmacodynamics, safety and tolerability as well as the pharmacokinetics of BAY 63-9044 in a randomized, single-blind, placebo-controlled group-comparison dose escalation study. 45 healthy men received BAY 63-9044 as an oral solution in single doses of 0.25 mg, 0.5 mg, 1.2 mg, 2.5 mg and 5.0 mg. Pupil reaction (baseline pupil diameter (DIAM), constriction amplitude (CA)), body temperature, electroencephalography (EEG) and prolactin, cortisol and adrenocorticotrophic hormone (ACTH) served as pharmacodynamic measures and were monitored up to 24 h after drug intake. Safety, tolerability and plasma samples for determination of BAY 63-9044 were followed up to 72 h. Up to a dose of 2.5 mg, BAY 63-9044 was safe and well tolerated. Dose-limiting adverse events (nausea, vomiting, and dizziness) occurred in 5 out of 6 volunteers at the 5 mg dose. Adverse events resolved spontaneously in all but one volunteers who was treated with an antihistaminergic for vomiting. Dose-dependent changes of DIAM and CA were observed at doses higher than 0.5 mg and 1.2 mg, respectively. Body temperature showed a trend for reduction starting at C(max) in the highest two doses only. No clear effect was found on prolactin, cortisol and ACTH levels. The pharmacokinetics of BAY 63-9044 showed a dose-dependent increase with maximum plasma concentrations reached within 1 h. Plasma concentrations declined in a bi-phased manner with an apparent terminal half-life of 5.2-8.1 h. Up to the maximum tolerated dose (MTD) of 2.5 mg BAY 63-9044 was safe and well tolerated and showed predictable linear pharmacokinetics. Pupil reaction may serve as a non-invasive biomarker for pharmacodynamic effects of 5-HT(1A)-compounds with DIAM being the most sensitive parameter.

An Open-label, Flexible-Dose Study of Memantine in Major Depressive Disorder

To assess the efficacy and safety of flexible-dose memantine in patients with major depressive disorder (MDD). In this 12-week, single-center, open-label study, 8 patients with MDD were titrated for 4 weeks to 20 mg/d memantine. Nonresponsive patients were titrated to 30 mg/d (at week 8) or 40 mg/d (at week 10), provided that no dose-limiting adverse events were observed. Outcome measures were the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale, the Clinical Global Impression-Severity of Illness and the Clinical Global Impression-Improvement Scales, the Patient Global Evaluation, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Major Depressive Episode Checklist. Tolerability and safety assessments were performed throughout the trial. The safety population comprised 8 outpatients with a mean (SD) baseline MADRS score of 31.9 (4.45), indicative of severe depression. Seven subjects completed the study. All patients attained the target dose of 20 mg/d; 3 patients were titrated to 30 mg/d after week 8, and 2 patients were titrated to 40 mg/d after week 10. The mean dosage across all weeks was 18.1 mg. Patients improved on all efficacy measures within 1 week of treatment initiation. The mean improvement peaked at week 8 and was maintained through week 12 (MADRS, 18.5 [10.3]; last-observation-carried-forward). All memantine doses were well tolerated. Memantine demonstrated early-onset efficacy in patients with MDD. The treatment was well tolerated. This study suggests that double-blind, placebo-controlled studies of memantine in depression are merited.

Thrombocytopenia Induced by CMC-544 and Its Amelioration Using Oprelvekin (Neumega®/Recombinant Human Interleukin-11).

CMC-544 is CD22-specific cytotoxic immunoconjugate of calicheamicin that has demonstrated significant anti-tumor activity in phase I clinical trial in B-NHL patients (Blood 2005; 106:230). In this trial, thrombocytopenia was reported as the most common dose-limiting adverse event. The present non-clinical study attempted to provide insights into the observed thrombocytopenia associated with CMC-544 treatment in B-NHL patients. In vitro, CMC-544 neither bound to nor caused aggregation of platelets in platelet-rich plasma of human or murine origin. When administered to mice, a single dose of CMC-544 resulted in a 50% to 75% reduction in the number of circulating platelets with a nadir on day 3 or 4. The platelet levels returned to normal at the latest by day 12. Similar effects were also observed in cynomolgus macaques with nadirs on day 4 or 5. CMC-544 dose not cross-react with either murine or cynomolgus macaque CD22. Unconjugated anti-CD22 antibody, G5/44 (humanized IgG4 antibody) had no effect on circulating platelets. CMC-544-induced thrombocytopenia in mice was associated with a concomitant reduction in circulating levels of thrombopoietin (TPO) with a nadir on day 4. In contrast, treatment with carboplatin, a cytotoxic chemotherapeutic agent known to cause thrombocytopenia, caused thrombocytopenia in mice but with a nadir on day 11. Unlike that with CMC-544, carboplatin-induced thrombocytopenia was associated with an increase in the levels of circulating TPO. Thus, CMC-544-induced thrombocytopenia appears to be mechanistically and kinetically distinct from that associated with conventional cytotoxic chemotherapeutic agents. In this murine model, pretreatment with human IGIV (Carimune) failed to prevent CMC-544-associated thrombocytopenia. However, subcutaneous pretreatment of mice with oprelvekin (Neumega/rhIL-11; 250 ug/kg) significantly reduced the magnitude of the CMC-544-associated thrombocytopenia. When evaluated in cynomolgus macaques, daily subcutaneous pretreatment with oprelvekin (125 ug/kg) for 5 days completely prevented CMC-544-associated thrombocytopenia and also suppressed elevations in serum hepatic aminotransferases associated with the CMC-544 treatment. Concurrent administration of oprelvekin with CMC-544 failed to prevent the initial thrombocytopenia but did accelerate complete recovery of platelets counts to the pretreatment levels and also suppressed elevations in serum hepatic aminotransferases. These results suggest that thrombocytopenia associated with CMC-544-treatment may in part be due to CMC-544-induced hepatic changes, including decreased TPO production. This study further provides evidence that oprelvekin not only stimulates megakaryocytes to produce platelets but is also hepatoprotective, reducing the degree of CMC-544-mediated hepatotoxicity. We have presented preclinical evidence that the prophylactic use of oprelvekin can ameliorate CMC-544-induced thrombocytopenia and thus, supports the clinical evaluation of oprelvekin administered with CMC-544 to augment its therapeutic benefit in patients with B-non-Hodgkin's lymphoma.

Dose‐Escalation Study of ICA‐17043 in Patients with Sickle Cell Disease

To determine the dose tolerance, safety, and pharmacokinetics of a single oral dose of ICA-17043 in patients with sickle cell disease. Phase I, randomized, double-blind, placebo-controlled, single-dose, dose-escalation study. Four university medical centers. Twenty-eight patients with sickle cell disease, aged 18-60 years, who were otherwise healthy and in a noncrisis state. Patients in three separate dose cohorts--50 mg, 100 mg, and 150 mg--received single doses of ICA-17043 or placebo. The mean area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)) for ICA-17043 increased in a dose-related manner (11,827, 19,697, and 30,676 ng.hr/ml for 50, 100, and 150 mg, respectively). Overall mean half-life was 12.8 days. Mean peak plasma concentrations rose between the 50- and 100-mg dose levels but plateaued at 150 mg (59.1, 108.7, and 109.1 ng/ml, respectively). Weekly pharmacokinetic and safety assessments were conducted in each patient during the follow-up phase for 56 days. No dose-limiting adverse events were noted in any of the patients. Total systemic exposure of ICA-17043 after a single oral dose, as measured by AUC(0-infinity), increased nearly proportionally with the dose. The rate of absorption, however, appeared to be delayed at doses greater than 100 mg. With the long half-life of ICA-17043 demonstrated in this study, once-daily dosing is probably adequate to maintain steady-state plasma concentrations. In addition, single doses of ICA-17043 were well tolerated.

Phase 1 study of atrasentan (ABT627), novel endothelin receptor-A antagonist, in Japanese patients with hormone refractory prostate cancer

14602 Background: Endothelin (ET)-1 and its primary receptor, the ETA receptor, contribute to tumor cell growth, survival, angiogenesis and invasion. Atrasentan is a highly potent, selective ETA receptor antagonist. This study assessed safety and pharmacokinetics (PK) in Japanese patients with hormone refractory prostate cancer. Methods: This open-label, single-center Phase I trial evaluated the safety and PK of escalating oral atrasentan doses (2.5, 10 or 20 mg) given daily on day 1 and day 4 through 27 (except day 2 and 3). Dose-limiting toxicity (DLT) was defined as Grade 3 or greater adverse events related to study drug. Results: Eighteen patients, aged 54–74 (median; 66) were treated in cohorts of 6 patients each. The compliance of all patients was 100%. The most common toxicities were rhinitis, peripheral edema, headache, hypotension and anemia, all of which were well tolerated. These events were consistent with the anticipated vasodilatory effects or with a hemodilution effect of the study drug. DLTs were not observed. Atrasentan was rapidly absorbed following oral administration of 2.5 to 20 mg, maximum plasma concentrations averaged from 0.4 to 0.8 hours. After peaking, plasma concentrations declined bi-exponentially with a terminal half-life of approximately 25 hours. In the 10 mg dosing group, the steady-state maximum plasma concentration (Cmax) and the area under the curve (AUC0–24h) averaged 135.5 ng/mL and 533 ng h/mL, respectively. The Cmax and AUC values generally increased linearly with increasing dose after single- and multiple-dose administration. Compared to baseline, PSA decreased 50% or more in 1 patient (20 mg) and increased 25% or more in 10 patients (2.5 mg;2, 10 mg;5, 20 mg;3). The PSA of the remaining 7 patients (2.5 mg;4, 10 mg;1, 20 mg;2) ranged from < 25% increase to < 50% decrease. Fourteen patients continued on study drug in an extension study. Conclusions: Atrasentan is well tolerated, with no dose-limiting adverse events observed up to 20 mg in Japanese patients. The main adverse events are consistent with the vasodilatory effect of the drug. PK are linear and dose-proportional; the half-life is appropriate for once-daily dosing. No significant financial relationships to disclose.

Albumin-Interferon-α in the Treatment of Chronic Hepatitis C

Despite advances in treating chronic hepatitis C, newer treatments are required. Albumin fusion technology allows the enhanced pharmacokinetic properties of albumin to be combined with the pharmacodynamic properties of other agents. Albumin-interferon-α has an extended half-life that supports bimonthly or monthly dosing and may provide superior steady-state exposure to interferon. Preclinical studies show that albumin-interferon has better antiviral activity and pharmacokinetics than either standard or pegylated interferons. Phase I–II and Phase IIa studies that have explored a wide dose range (from 10 to 1200 μg) in interferon-experienced and -naïve patients have shown the drug to be safe and well tolerated, with no dose-limiting adverse events. Its half-life is 6–7 days and it is detectable 4 weeks after a single dose. The longer term safety and efficacy of albumin-interferon and ribavirin is being evaluated in both interferon-naïve patients and nonresponders to previous standard and pegylated interferon therapy.

726. Clinical Trial of Recombinant Adenovirus-p53 (Gendicine) Combined with Radiotherapy in Nasopharyngeal Carcinoma Patients

The study was to evaluate the safety and the efficacy of recombinant adenovirus-p53 (Adp53, trademarked as Gendicine) combined with radiotherapy in nasopharyngeal carcinoma (NPC) patients. A controlled clinical trial on Gendicine combined with radiotherapy, that is, gene therapy + radiotherapy (GTRT), was conducted in 24 patients, and 25 patients treated with radiotherapy alone (RT) formed the control group. In the GTRT group, Gendicine 1|[times]|1012 virus particle (vp) was intratumorally injected once a week over to eight weeks, and concurrent irradiation was given. For both groups, the conventional fractionation 2Gy/day, five fractions a week, with a total dose of 70Gy in 35 fractions were given to either primary tumor or neck lymph node. Patients were monitored for adverse event and serum anti-adenoviral antibody, and tumors were monitored for response. A comparative study was performed between both groups on the immediate response rate by CT at the end of 4th week, 7th week and 2 months after the treatment. The median follow-up interval of surviving patients was 34.5 months (24|[sim]|45 months). Wild-type p53 gene therapy enhanced significantly radiotherapy efficacy by 1.59 times in patients with NPC at 4- week time point. Two months after the treatment complete response rate of GTRT group was 2.1 times that of RT group (62.5% v.s. 29.6%). The 3-year overall survival rate of GTRT group was 14.4% higher than that of GT group. No dose-limiting toxicity and adverse events were noted, except for transient fever after Gendicine administration. Intratumoral injection with Gendicine was safe and effective for patients with NPC.

Clinical study of recombinant adenovirus-p53 (Adp53) combined with hyperthermia in advanced cancer (a report of 15 cases)

The study was to evaluate the efficacy of the Adp53 combined with hyperthermia on advanced cancer. Fifteen patients with advanced cancer were enrolled in this clinical trial. Thirteen patients with recurrent tumours failed in conventional treatments and the two other patients with primary tumour received no treatment before they were enrolled. Recombinant adenovirus-p53 (Adp53) is a E1 substituted replication-incompetent recombinant adenovirus encoding the human wild-type p53 (wtp53) gene. The 15 patients were intra-tumourally injected with Adp53, 1 × 1012 vp (virus particle) once a week, with a total of 4 ∼ 8 times was given. The temperature being set hyperthermia every week 3 days after the injection of Adp53 at 43 ∼ 44°C using 915 MHz microwave machine for superficial tumour for 1 h or at 42 ∼ 43°C using 41 MHz radiofrequency machine for deep-seated tumour for 1 h. Among the 15 patients, five concurrently were added with radiotherapy and three were added with cisplatin-based chemotherapy. The treatment achieved CR in two cases, PR in four cases, SD in eight cases and PD in one case and, after the treatment, tumours of two cases disappeared and seven of the other 13 cases (54%) had low-density area (LDA) of more than 50% on CT images in tumours. In the 15 patients, no dose-limiting toxicity and adverse events were noted, except transient fever after Adp53 administration. In conclusion, Adp53 combined with hyperthermia was safe and effective in patients with advanced cancer and p53 gene therapy was potential to thermosensitize in advanced cancer.

Community-Based Multicenter Evaluation of Subcutaneous Amifostine

Purpose/Objective: Amifostine is an aminothiol prodrug that protects mucosal tissue from radiotoxicity. Intravenous administration, the approved route, presents logistical difficulties for many practices and can cause dose-limiting adverse events (AEs). Subcutaneous (SC) administration may offer greater ease of administration with an acceptable toxicity profile.

Pharmacokinetics (PK) and pharmacodynamics (PD) of E7820-an oral sulfonamide with novel, alpha-2 integrin mediated antiangiogenic properties: Results of a phase I study

3082 Background: : E7820 is a first in class orally administered antiangiogenic sulfonamide that inhibits alpha-2 integrin. E7820 is a potent inhibitor of endothelial cell proliferation and vascular tube formation in vitro, and it effectively inhibits the growth of human breast and pancreatic cancer xenografts. Methods: This open-label, non-randomized phase I study of E7820 in patients (pts) with metastatic and/or recurrent solid tumors utilizes a standard dose escalation design to evaluate the safety and to determine the maximum tolerated dose of daily oral administration of E7820. Secondary objectives include characterization of the PK profile, assessment of PD markers (DCE-MRI, VEGF and bFGF levels in plasma and serum, and changes in alpha-2 integrin expression in circulating platelets), and preliminary exploration of antitumor activity. Results: To date, 18 pts (13 male/5 female; median age 68 [range 40–80]), have been treated with E7820 at doses ranging from 10 to 100 mg/day. No dose-limiting toxicity or E7820-related serious adverse events have been observed. Pts received a median of 3 cycles (range 1–8). Side effects include: grade 1 or 2 fatigue, anorexia, constipation, diarrhea, nausea, vomiting, dizziness, maculopapular rash, mucositis, liver enzymes elevation, paresthesia, and fever. No objective responses have been observed to date. Five pts had stable disease lasting from 3 to 7+ months, and 4 pts continued therapy for 4+ cycles. PK data up to 70 mg demonstrate a Tmax at 2 hr, a dose-dependent increase in both Cmax and AUC, an accumulation factor ranged from 1.08 to 1.82 with higher values seen at the 70 mg dose level and a half-life of 5.7 to 11.9 hr. The Cmax at doses above 70 mg/d approaches the concentrations active in vivo in preclinical models. Conclusions: E7820 at doses up to 100 mg/day has an excellent safety profile in pts with solid malignancies. Enrollment to higher dose levels and analysis of PD endpoints are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Global Clinical Eisai Eisai

A Phase 1 Study of PAmAb, a Fully Human Monoclonal Antibody against Bacillus anthracis Protective Antigen, in Healthy Volunteers

Inhibition of the binding of Bacillus anthracis protective antigen (PA) to its cellular receptor can abrogate the downstream toxin-mediated deleterious effects of the anthrax toxin. A fully human monoclonal antibody against B. anthracis PA, PAmAb, was previously shown to provide a survival advantage in rabbit and monkey models of inhalational anthrax. A randomized, single-blind, placebo-controlled, dose-escalation study with 105 healthy volunteers was conducted to evaluate the safety, pharmacokinetics, and biological activity of PAmAb. Subjects received PAmAb or placebo as a single intramuscular injection (11 subjects/cohort) or intravenous infusion (10 subjects/cohort). Three intramuscular dose levels (0.3, 1.0, and 3.0 mg/kg) and 5 intravenous dose levels (1.0, 3.0, 10, 20, and 40 mg/kg) were studied. Two separate intramuscular injection sites (gluteus maximus and vastus lateralis) were evaluated in the cohorts (hereafter, the "IM-GM" and "IM-VL" cohorts, respectively). PAmAb was well tolerated, with no dose-limiting adverse events. All adverse events were transient and mild to moderate in incidence and/or severity. The pharmacokinetics of PAmAb were linear within each route and site of administration but were significantly different between the IM-GM and IM-VL cohorts. The mean terminal elimination half-life ranged from 15 to 19 days. The bioavailability of PAmAb is approximately 50% for IM-GM injection and 71%-85% for IM-VL injection. The biological activity of PAmAb in serum, assessed using a cyclic adenosine monophosphate assay, correlated with serum concentrations. PAmAb is safe, well tolerated, and bioavailable after a single intramuscular or intravenous dose, which supports further clinical development of PAmAb as a novel therapeutic agent for inhalational anthrax.

Effects of hydration with salt repletion on renal toxicity of conventional amphotericin B empirical therapy: a prospective study in patients with hematological malignancies

Several studies have suggested that hydration and sodium load might reduce nephrotoxicity related to amphotericin B-deoxycholate (AmB-d). However, a schedule of these nephroprotective measures has not been standardized until now. A protocol of hydration and electrolyte supplementation was used prospectively in patients with hematological malignancies receiving empirical AmB-d treatment to evaluate its effect on AmB-d-related renal toxicity. A total of 77 consecutive patients received AmB-d (1 mg/kg per day) in association with an initial intravenous hydration of at least 1 l/m2 body surface, containing at least 1 l of 0.9% saline daily. Hydration was increased when serum creatinine levels showed a 20% increase from baseline. Serum electrolytes were replaced when indicated. The median duration of AmB-d therapy was 14 days. The mean intravenous hydration and the mean diuresis were 1530 and 1970 ml/m2 of body surface per day, respectively. Overall, 55 patients (71.4%) received a mean of 18.5 days of therapy without dose-limiting adverse events. Despite significant increases in mean creatinine serum levels and decreases in mean creatinine clearance observed early in the whole population, in only six patients (7.8%) was therapy discontinued due to renal failure, which always recovered after treatment discontinuation. In eight patients (10.4%) therapy was stopped due to infusion-related side effects. Seven patients died while under antifungal therapy without relevant signs of AmB-d-associated toxicity. Our prospective experience confirms that adequate hydration (about 1500 ml/m2 of body surface) and careful electrolyte supplementation are simple measures able to contain nephrotoxicity and to permit adequate antifungal therapy at least in the empirical setting.

Pharmacokinetics and genotypes do not predict metoprolol adverse events or efficacy in hypertension

Beta-Blocker use can be associated with adverse effects that may have an impact on adherence or harm patients. The commonly prescribed beta-blocker metoprolol is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 enzyme, resulting in widely variable drug exposure. We investigated whether metoprolol plasma concentrations, CYP2D6 polymorphisms, or genotype-derived phenotype was associated with adverse effects or efficacy in patients with hypertension. Fifty hypertensive patients received metoprolol by use of a dose-titration algorithm until target blood pressure was reached, intolerable side effects occurred, or maximal daily dose was achieved. CYP2D6 genotype was determined by methods based on polymerase chain reaction-restriction fragment length polymorphism and included 19 allelic variants. Patients were assigned to standard phenotype groups on the basis of genotype. Patients were also assigned activity scores based on functional activity of the alleles. General and dose-limiting adverse events and blood pressure responses were analyzed in relation to metoprolol steady-state pharmacokinetic profile and CYP2D6 genotype-derived phenotype. Poor metabolizers had a significantly longer elimination half-life, higher S-metoprolol area under the plasma concentration-time curve (AUC), and lower oral clearance (P < or = .007 for all parameters). There was a 29.6-fold variability in AUC among extensive metabolizers, which was largely explained by CYP2D6 activity scores (P = .032 for ordered differences in AUC by activity score among extensive metabolizers). Overall general and dose-limiting adverse event rates were 46% and 14%, respectively. General adverse event rates did not differ by AUC quartile (66.7% [95% confidence interval (CI), 35.4%-88.7%] and 41.7% [95% CI, 16.5%-71.4%] in the lowest and highest quartiles, respectively; P = .09 among all quartiles). Dose-limiting adverse event rates were also not different by AUC quartile (16.7% [95% CI, 2.9%-49.1%] and 8.3% [95% CI, 0.4%-40.2%] in the lowest and highest quartiles; P = .35 among all quartiles). Furthermore, adverse event rates did not differ by activity scores or between extensive, intermediate, or poor metabolizers. Antihypertensive response rate and blood pressure changes also were not influenced by differences in plasma concentrations or CYP2D6 genotypes. As expected, CYP2D6 genotype-phenotype correlates with differences in metoprolol pharmacokinetics. However, there was no association between variable pharmacokinetics or CYP2D6 genotype and beta-blocker-induced adverse effects or efficacy.

Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily X 5 every other week in patients (pts) with refractory or advanced malignancies

3076 Background: AP23573, a non-prodrug rapamycin analog, potently inhibits mTOR, a downstream effector of the PI3K/Akt and nutrient signaling pathways. AP23573 demonstrated potent inhibition of proliferation in vitroin several human tumor cell lines and elicited antitumor activity in vivo in multiple xenograft animal models. Methods: This dose escalation trial utilizes an accelerated titration scheme to determine safety, tolerability and maximum tolerated dose of AP23573 administered without premedication as 30-minute IV infusion daily x 5 days every 2 weeks for 4-week cycles. It also is designed to characterize the PK profile, evaluate potential PD markers using western blot analysis of peripheral blood mononuclear cells (PBMCs) and immunohistochemical analysis of skin biopsies, and ascertain preliminary data on antitumor activity. Results: As of 01 Dec 03: 11 pts (6M/5F), median age 57 yrs (range 23–65 yrs), were treated with AP23573 doses ranging from 3 to 28 mg in 5 dose level cohorts (total cycles, 32; median cycles, 2/pt). No dose-limiting toxicity or AP23573-related serious adverse events have been observed. Side effects for first cycle included grade (gr) 2 anemia (2 pts); gr 3 transient transaminase elevation (1 pt with hepatocellular cancer); gr 2 mucositis (2 pts); gr 1 skin rash (2 pts). PK analyses (doses 3 to 12.5 mg) suggest a mean AP23573 half-life of 44–54 hours. PD analyses (doses 3 and 6.25 mg) indicate rapid (within 1 hr) and prolonged (up to 10 days between doses) inhibition of mTOR activity as demonstrated by >80% decrease in phosphorylated 4EBP1 levels in PBMCs. Of 8 evaluable pts, one partial response has been observed in a pt with metastatic renal cell cancer; (6.25 mg) and 1 pt with metastatic sarcoma (3 mg) has had stable disease > 6 months. Conclusions:AP23573 can be administered safely using this schedule, and has exhibited antitumor activity as well as evidence of a substantial PD effect. Patient dosing and enrollment are ongoing. Further dose escalation as well as exploration of the relationship between PD (PBMC and skin) and PK are planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc.